Received: 27 June 2020 Revised: 4 October 2020 Accepted: 6 October 2020

DOI: 10.1002/bies.202000163

P ROB L EM S & PA RAD I GM S

Prospects & Overviews

Accounting for variation in and overuse of antibioticsamong humans

Martin J. Blaser1 Melissa K.Melby2 Margaret Lock3 Mark Nichter4

1 Center for Advanced Biotechnology andMedicine, Rutgers University, Piscataway, New Jersey, USA

2 Department of Anthropology, University of Delaware, Newark, Delaware, USA

3 Department of Social Studies ofMedicine andDepartment of Anthropology, McGill University, Montreal, Quebec, Canada

4 School of Anthropology, Mel and Enid Zuckerman College of Public Health, Department of FamilyMedicine, University of Arizona, Tucson, Arizona, USA

Correspondence

Martin J. Blaser,Center forAdvanced

BiotechnologyandMedicine, Rutgers

University, PiscatawayNJ08854,USA.

Email:martin.blaser@cabm.rutgers.edu

MarkNichter, School ofAnthropology,Mel

andEnidZuckermanCollegeofPublicHealth,

Departmentof FamilyMedicine,University of

Arizona, TucsonAZ85721

Email: nichtermark@gmail.com

Funding information

FondationLeducq;Canadian Institute for

AdvancedResearch;C&DFunds;National

InstitutesofHealth,Grant/AwardNumber:

U01AI22285

Abstract

Worldwide, antibiotic use is increasing, but many infections against which antibi-

otics are applied are not even caused by bacteria. Over-the-counter and internet sales

preclude physician oversight. Regional differences, between andwithin countries high-

light many potential factors influencing antibiotic use. Taking a systems perspective

that considers pharmaceutical commodity chains, we examine antibiotic overuse from

the vantage point of both sides of the therapeutic relationship. We examine patterns

and expectations of practitioners and patients, institutional policies and pressures, the

business strategies of pharmaceutical companies and distributors, and cultural drivers

of variation. Solutions to improve antibiotic stewardship include practitioners taking

greater responsibility for their antibiotic prescribing, increasing the role of caregivers

as diagnosticians rather than medicine providers, improving their communication to

patients about antibiotic treatment consequences, lessening the economic influences

on prescribing, and identifying antibiotic alternatives.

INTRODUCTION

The global consumption of antibiotics is rapidly increasing as is con-

cern about antibiotic resistance [1–4] as a collective ecological con-

dition of late industrialism [5–7] and as a modern day tragedy of the

commons.[7–9] As such, antibiotic use demands stewardship on both

a local and global scale.[10,11] Despite their undisputed benefits in

patients with clear-cut and life-threatening bacterial infections, it is

widely acknowledged that antibiotics are both grossly misused and

overused [2,3,12] leading to drug resistance, and to pernicious effects

on the microbiome that place users at greater risk for a growing list

of health conditions.[13–16] Unnecessary antibiotic treatment also con-

stitutes an economic burden to both health care systems and to fam-

ilies when medications are paid out of pocket. This burden increases

when antibiotic resistant infections emerge given that they take longer

to treat, aremore costly, and often associated with worse outcomes.

In this paper, we provide a brief overview of antibiotic use in both

developed and low and middle-income countries (LMIC), highlighting

regional differences. Our focus is on what drives antibiotic overuse.

We consider the prescription practices of different types of health care

practitioners and medicine dispensers as well as the self-treatment

practices of community members. Taking a systems perspective that

considers pharmaceutical commodity chains, we examine antibiotic

overuse from the vantage point of both sides of the therapeutic rela-

tionship, institutional policies and pressures, and the business strate-

gies of pharmaceutical companies and distributors. Our major concern

is on antibiotics imbibed among out-patients, since it represents the

majority of all usage, and because in-hospital antibiotic use involves

greater complexity in sicker patients. Our review draws upon studies

of human antibiotic use conducted by researchers from several disci-

plines. Based on our review, we offer suggestions on how to improve

antibiotic stewardship.

BioEssays. 2021;2000163. © 2021Wiley Periodicals LLC 1 of 18wileyonlinelibrary.com/journal/bies

https://doi.org/10.1002/bies.202000163

2 of 18 BLASER ET AL.

ANTIBIOTIC CONSUMPTION AND VARIATION INOVERALL USE

Global trends in antibiotic use

Direct antibiotic use for humans in 2011 was estimated at 70 billion

doses, or approximately ten antibiotic doses annually for every man,

woman, and child on earth.[12] At a global level, antibiotic consump-

tion has been steadily increasing; between 2000 and 2015, antibi-

otic consumption increased 39% globally, reflecting a 77% increase

among LMICs, more than offsetting a 4% decrease among high-

incomecountries (HICs).[2] Antibiotic usage rates arehighest for young

children.[17–24] Young children, at critical developmental stages, are

commonly exposed to antibiotics in low-income settings. As reported

from a large longitudinal household-based study, children from eight

LMIC countries consumed an average of 4.9 antibiotics courses annu-

ally during the first two years of life.[25]

Children usually suffer from4 to6upper respiratory tract infections

(URIs) annually compared to two to three episodes in adults.MostURIs

are self -limited and at least 80% are not caused by bacteria.[26] How-

ever, URIs are the most common ailments treated by antibiotics,[27]

especially in young children. In China, 78% of outpatient children

with the common cold received an antibiotic prescription,[28] and in

Turkey, 100% of children presenting to an emergency room with an

influenza-like illness were prescribed an antibiotic.[29] Notably, even

in the USA, where antibiotic prescriptions for children have dropped

substantially over the last two decades, unnecessary prescriptions

of antibiotics remain high,[30] and there is significant variation by

practitioner.[31]

Data consistently show high prescription rates. In a large study

in China, the antibiotic prescription rates in acute upper respiratory

infections, diarrhea in children<5 years, and fever or cough symptoms

all exceeded 55%.[32] In the eight-LMIC country study,[25] antibiotics

were used in about 40% of all episodes of either upper respiratory ill-

ness or (non-bloody) diarrhea. In a prospective observational cohort

study in South India, more than half the children had been treated

withantibiotics for respiratory infectionsordiarrhea;most (89.2%)had

received antibiotics by the age of 6months. Although there is little con-

sideration of the biological costs of antibiotic use, there is great con-

cern that the health benefits of widespread antibiotic availability for

poor childrenwill bemissed if use is restricted.[33]

Emerging trends include internet sales; studies in the USA, UK,

and China have found numerous online pharmacies selling antibi-

otics without a prescription or after providing a cursory pre-sale

consultation.[34–37] Another source of questionable antibiotic sales

are primary consultations over the telephone; in an analysis of recent

calls with complaints of an acute respiratory infection to a direct-

to-consumer telemedicine service in the USA, 86% of the telephone

prescriptions were for a broad-spectrum agent compared to 56%

for physician offices.[38] However, high-quality longitudinal data in

the United States also has documented significant shifts in antibiotic

use. Outpatient antibiotic consumption, as measured by expenditure,

decreased 16.6% from 2010 to 2015.[39] Similarly, the proportion of

people who reported using an antibiotic in the prior 30 days declined

from 1999–2002 (6.1%) to 2011–2012 (4.1%).[40]

The distribution of the classes of antibiotics consumed also

is changing. In 2000, broad-spectrum penicillins were the most

widely prescribed antibiotics in the world; the growth in usage

by 2010 was mostly driven by increases in broad-spectrum peni-

cillin, cephalosporins, macrolides, and fluoroquinolones.[12] However,

global trends reflect a composite of regional differences; for example,

cephalosporin consumption rose in LMICs but declined in HICs, as did

consumption of other broad-spectrum agents such asmacrolides, fluo-

roquinolines, and oxazolidiones (Figure 1).[2] Thus, global trends often

hide local practices.

Differences in prescription patterns by region

In the USA, there is substantial geographic variation in out-patient

antibiotic consumption (Figure 2, panel B).[20] Consumption rates are

highest in the South and lowest in the West, with the Northeast and

Midwest being intermediate in consumption; these trends have been

consistent over time, and are essentially the same for all age groups.[19]

Similarly, antibiotic prescriptions given in physicians’ offices in 2012–

2013 for respiratory conditions were lowest in the Pacific region and

highest in the East South-Central region, a trend also observed for the

rates at which respiratory illnesses were diagnosed.[41] Such variation

also was seen in commercial health plans, with those in the South Cen-

tral census division showing the highest use of three antibiotic-related

measures.[42] In total, the national-level data indicate consistent geo-

graphic variation that is stable across multiple years and patient ages.

The differences are not small; per capita antibiotic use in the South

is more than 50% higher than in the West, across tens of millions of

people,[20,21] and are consistent across different data bases.[43]

Similar to the US, overall antibiotic consumption decreased signifi-

cantly inEurope from1997 to2009.[44,45] Nevertheless, there is exten-

sive variability in usage between countries; with two-fold differences

in per capita consumption between countries bordering the Mediter-

ranean (Greece, Cyprus, Italy and France), and northern European

countries (Netherlands, Sweden, Norway, Germany)[44] [Figure 3].

Several cross-country comparisons are also worth considering.[2,12]

For example, data from Sweden documents annual per capita antibi-

otic consumption that is only 40% of that in the USA; a pattern that

holds true across every age group.[21,46] Further, Swedish outpatient

usage of macrolides and cephalosporins (at 3% each of the total), con-

trasts with 23% and 14%, respectively, for the USA.[39] As in the USA,

antibiotic use fluctuates with season, the highest use being in the win-

ter months (Figure 4). In general, the countries that have the highest

rate of total use also had the largest seasonal differences in antibiotic

use.

In contrast to the USA and most of Europe, a high proportion of

antibiotics sold in LMIC countries is without prescriptions at local

pharmacies.[47] These shops are often staffed by untrained attendants

who commonly dispense only a few antibiotic pills at a time at a cus-

tomer’s request. A metanalysis of 38 studies from 24 countries where

BLASER ET AL. 3 of 18

F IGURE 1 Changes in global consumption of eight different classes of antibiotics between 2000 and 2015, stratified by level of countryincome: high-income (HIC), low- and upper-middle-income (LMIC-UM), low- & lower-middle-income (LMIC-LM) [reprinted fromKlein 2018][2]

F IGURE 2 Comparison of opiate prescribing, antibiotic prescribing, and rates of church attendance, by state, in the USA. Panels: (A) Opiateprescribing rates are per 1000 population in 2012 (reprinted from Paulozzi 2014[178]). (B) Antibiotic prescribing rates per 1000 population(reprinted fromHicks et al. 2013 [20]); the same trends held in 2011, and as well when the population was stratified by age (children<2 years, age2–64 years, elderly (>65) [reprinted fromHicks Clin Infect Dis 2015][19]; (C) Church attendance rates are per 100 adults in 2014 [reprinted fromPew, 2014][148]

antibiotics are technically available by “prescription only” found that

the overall proportion of non-prescription supplied antibiotics was

62%, due both to patient request and pharmacy staff recommendation.

Antibiotic dispensing by pharmacy staff oftenmirrors practitioner pre-

scribing, since they are aware of the actual prescriptions. These pat-

terns are then reproducedbyuntrained localmedical practitionerswho

purchase medicines from the same local pharmacies using them as a

source of information as well as supply.[48,49] The scale of this issue is

substantial in countries such as India where these “doctors” see up to

75% of primary care consultations in rural areas.[50–55] Although sales

of several antibiotics classeswithout prescription are technically illegal

in many LMIC, enforcement is difficult in rural areas with few doctors

4 of 18 BLASER ET AL.

F IGURE 3 Antibiotic consumption in Europe in 2009 by antibiotic class [reprinted fromAdriaenssens, 2011][44]

F IGURE 4 Seasonal fluctuations in antibiotic use in 10 European countries, 1997 to 2002, highlighting winter peaks [reprinted fromGoossens2005][45]

BLASER ET AL. 5 of 18

and in urban settings where the poor consult pharmacy staff for com-

mon ailments.

FACTORS DRIVING VARIATION IN ANTIBIOTIC USEAND OVERUSE

Studies have identified a wide range of practitioner, patient, health

system, and pharmaceutical industry-related factors contributing to

differences in rates of antibiotic misuse and overuse. Quantitative

studies largely provide correlational data while qualitative studies

provide more contextual and processual accounts of how multiple

factors act in concert and reflect broader cultural considerations.

We briefly highlight well-documented drivers of antibiotic overuse

and identify other potential factors influencing the pharmaceutical

practice of both trained practitioners working in different clinical

practices, and untrained local “doctors” and dispensing pharmacy staff.

Variation according to characteristics of practitioners

A critical aspect of prescription practices is provider-level variation. In

a large national study of acute respiratory infections among US veter-

ans, the10%of providerswhoprescribed themost antibiotics provided

an antibiotic in at least 95% of their visits versus <40% for the lowest-

rate prescribers.[56] In a study examining 29 pediatric group practices

affiliated with an outstanding teaching hospital in the USA, the varia-

tion in per capita antibiotic prescribing between the practice that pre-

scribed the least and the one prescribing themost exceeded 100%, and

for broad-spectrum antibiotics, 400%.[31]

The age of practitioners has been correlated with the likelihood of

an antibiotic prescription. A USA-based study of pediatric outpatient

visits for common upper respiratory conditions that do not require

antibiotics found that older providers were four times more likely to

prescribe an antimicrobial than providers ≤30 years old (IRR, 4.21;

95%CI, 2.96–5.97).[57] Similarly, in a study of more than 10,000 family

physicians in Ontario who collectively prescribed 5.6 million antibiotic

courses, the number of physician years in practice was an important

determinant of the duration of antibiotic courses. Prescriptions of

longer duration (>8 days) were disproportionately prescribed by late-

career physicians (in practice>25 years) (38.6%of their total antibiotic

prescriptions) compared to mid-career (11–25 years) (34.4%), or early

career (<10 years) physicians (30.5%).[58] Taken together, these

findings are consistent with the hypothesis that older physicians have

greater reliance on antibiotics than their younger colleagues, pointing

to opportunities for educational interventions.

Antibiotic choices also vary by practitioner type. Azithromycin is the

most commonly prescribed antibiotic in the United States, although it

is infrequently recommended for pediatric conditions.[59,60] However,

in a national study of oral antibiotic use, amoxicillin and azithromycin

were the two most commonly prescribed agents in children. Most

antibiotics for children were prescribed by pediatricians (39%) and

family practitioners (15%), but family practitioners were significantly

more likely to prescribe azithromycin than pediatricians, across all ages

in childhood.[59,61,62]

Nurse practitioners (NPs) and physician assistants (PAs) in the USA

prescribe antibiotics more frequently compared with physician-only

visits, including visits overall (17% vs. 12%, P < 0.0001) and for acute

respiratory infections (61% vs. 54%, P < 0.001).[63] While the antibi-

otic prescribing rate among physicians in the US decreased from 2005

to 2010, it increased for PAs and NPs,[63] providing another target

group for educational efforts. Free-standing out-patient clinics (“doc-

in the-box”) havebeen a rapidly increasing venue for patient care; often

staffed with PAs andNPs, antibiotic prescribing is at high rates.[63]

Variation according to public understanding of theneed for antibiotics

Studies from around the globe have documented that the public is

poorly informed about which common health problems are cured

by antibiotics, whether antibiotics are effective against all types of

“germs,” and which illnesses are of viral or bacterial origin.[55–57] For

example, most Australian parents believed that antibiotics are needed

for children’s common respiratory infections: for acute otitis media

(92%), sore throat (70%), and cough (55%).[64] In Italy, 41% of parents

believed that bacteria are a cause of the common cold, treatable by

antibiotics.[65] In a Polish study,[66] 80% of respondents recognized

that antibiotics “kill” bacteria, but many believed that antibiotics also

kill viruses (60%), and are effective against flu (49%), and colds (36%).

Across Europe, 57% of those surveyed were unaware that antibiotics

were ineffective against viruses, and 44% did not know that antibiotics

have no effect against colds or influenza.[67,68] In a North Carolina

study, 53% of respondents incorrectly believed that antibiotics are

effective for treating flu or the common cold, which did not differ sig-

nificantly by sex, family status, or education level.[69] In an inner–city

emergency department in the USA, 75% and 42% of patients believed

that antibiotics were effective against bacterial and viral illnesses,

respectively. Many lumped all types of pathogens together adopting a

“germs are germs“ attitude.[70] And among those who differentiated

the two types of infection, many still accepted a “why take a risk” or

“can’t hurt” position about taking antibiotics, reflecting attitudes of

many practitioners.

Another observation pertains to how patients respond to doctors

when told their illness is caused by a virus and that they are not in

need of antibiotics. Some patients interpret a virus diagnosis as a “just

a virus” message, which trivializes their illness.[71] Recognizing this,

some doctors are inclined to prescribe an antibiotic to maintain good

social relations with the patient; the symbolic act of prescribing a

medicine eclipses treatment guidelines.[72]

In LMIC, antibiotics are often seen as “strong,” magical medicines,

capable of both curing and preventing a range of illness.[73] However,

there is considerable confusion among the public about which drugs

are antibiotics.[74,75] The Philippines has one of the highest levels

of antibiotic self-medication in Southeast Asia, consistent with easy

access in both urban and rural areas at local provision (sari sari)

6 of 18 BLASER ET AL.

shops and pharmacies. Study participants (>80%) often believe that

antibiotics are effective against cough or cold.[76]

Antibiotics are commonly used to self-treat health problems for

which they were never intended (off-label use). Examples include: (i),

in China, the actions of antibiotics and nonsteroidal anti-inflammatory

drugs are often conflated, as Xiaoyanyao, drugs that can eliminate

inflammation,[77–80] leading to antibiotic use for conditions with

self-limited inflammation; (ii), in Nigeria, women are increasingly

using antibiotics to reduce menstrual problems (cramps, heavy flow,

headaches, pimples/acne, moodiness, tender breasts, backache, joint

and muscle pain) and to prevent “infections” from feminine sanitary

products [81,82]; (iii), in Thailand, tetracycline is commonly used for

women’s “uterus” complaints, termedmoot luuk, manifesting as vaginal

discharge and pelvic pain [83,84]; and (iv), a common (world-wide) prac-

tice is self-treatment ofwoundswith crushed antibiotic capsules to dry

them, reduce pain, and treat infection.[76,85–89]

A common behavior adopted in many countries is taking antibiotics

to enable one go towork or school when ill,[90] or to delay illness onset

when feeling off until the weekend, or to prevent a “bug going around.”

Among Chinese university students, 29.6% had self-medicated with

antibiotics in the prior year, 23% had used antibiotics for prophylaxis

against illness [91]; and amajority (63%) kept a personal antibiotic stock

athome. Someworkers, at theeconomicmargin, takeantibiotics topre-

vent latent illness from flaring up given that their survival depends on

being able towork.[92] For example, in theUSA, left-over antibiotics are

taken by those employed in jobs that have fixed sick-leave provisions

and high job insecurity to manage respiratory symptoms from getting

worse, prevent others from catching their illness, or to prevent illness

when coworkers are ill.[93]

Another pattern of antibiotic prophylaxis is harm reduction. In the

Philippines and Thailand, antibiotics are commonly used by both com-

mercial sex workers and their clients for protection before or after

risky practices.[94–96] In China, commercial sex workers routinely take

antibiotic injections for harm reduction.[97] In India, young men fear-

ing theymay be developing an STI after unprotected sex self-treat with

an antibiotic purchased at a pharmacy when they feel vague bodily

sensations.[98]

Patient expectations and the pressure to prescribe

One of the most important factors linked to overprescribing antibi-

otics is patient expectations.[99,100] Physicians’ perceptions of what

patients expect during a consultation have been strongly associated

with antibiotic prescribing[65,101–105] and often described in the liter-

ature by the rubric “patient pressure.” Doctors’ perceptions of patient

expectations may be accurate or far exceed patient requests and

demands.[99,106–108] However, practitioners who have sufficient time

to educate and reassure patients, especially when they have an estab-

lished relationship, often are able to reassure patients antibiotics are

not needed.[109–111] For example, in a German study of patients with

upper respiratory tract infections,[112] 71% of those expecting an

antibiotic prescription reported that theywould trust their physician if

an explanation were provided for why a prescription was unnecessary,

and a further 7% reported that although unsatisfied, theywould accept

the decision; nevertheless,>20%would remain unsatisfied.

Patient “pressure” is often indirect and strategic. Patients may not

demand antibiotics outright, but rather infer their need through the

way they present the severity and prolonged nature of an illness, state

that antibiotics worked in the past for a similar problem, or by refer-

ence to life circumstance, such as an upcoming trip, or a work-related

event [113–115]; this is particularly an issuewithminor infections involv-

ing the respiratory tract, which are among the most common reasons

that patients seek medical attention.[112] In the USA, practitioners are

commonly faced with a mother’s appeal for an antibiotic enabling her

to return to work lest she lose her job, or to treat a sick child’s ill-

ness enabling them to return to school or day care.When practitioners

receive indirect pressure to prescribe, they often comply to maintain

good social relations with the patient and to reassure them that their

complaint is being taken seriously.[116]

While practitioners vary in their response to perceived patient

demands, many prescribe against their own assessment of patient

need. In a systematic review, perception that the patient had adesire to

receive antibioticswas oneof only two factors strongly associatedwith

prescribing (the other being a diagnosis of bronchitis).[103] These find-

ings suggest that only educating physicians about medical best prac-

tices and the population-based consequences of antibiotic overusewill

notbe sufficient to curtail use in their everydaypractices; educating the

public is crucial.

Notably, in a systematic review, physician attitudes about their

patients’ expectations were found to affect their prescribing practice

more than socio-demographic and personal factors [104]; complacency,

defined as fulfilling what the physician perceived as the expectation,

strongly drove prescribing, and fear of complications in the patient

played a smaller role.[117] In a study involving 305 UK family physi-

cians, doctors were presented with hypothetical patients; the increas-

ing expectation from a patient that they would receive an antibiotic

increased the physicians’ willingness to prescribe, although prescrib-

ing antibiotics did not indicate that they thought the infection was of

bacterial origin.[118]

Physicians caring for children are more likely to diagnose a bacte-

rial illness and are much more likely to prescribe antibiotics if they

believe that parents expect antibiotics. This is not a rare event, since

in a US study, 43% of parents of a child with cold symptoms believed

that antibiotics were necessary.[119] Such a belief was more frequent

among Latino and Asian parents than in Caucasians. In the US, eth-

nicity and language variation are associated with differences in basic

knowledge about antibiotics. In a Colorado survey, for example, non-

Hispanic Whites had greater knowledge of appropriate antibiotic use,

and English-speaking Hispanics had better knowledge than Spanish-

speaking Hispanics.[120] However, there does not appear to be sub-

stantial ethnic variation in the US in the frequency of non-prescription

antibiotic use,[121] and a systematic review of antibiotic-prescribing

determinants that assessed ethnicity found no associations in most

studies.[103] Nevertheless, ascertainment of availability from non-

traditional providers (e.g., bodegas) is incomplete.

BLASER ET AL. 7 of 18

Variation due to specific social and economicinteractions of prescribers and patients

Of the four most common factors reported to influence antibiotic

over-prescription, three include practitioner time pressure, practi-

tioner fatigue, and perceived patient expectation.[108,122–125] In a

survey of 187 physicians working in retail clinics and primary care

practices, inappropriate antibiotic prescribing was associated with

feeling rushed; physician knowledge of guidelines did not predict

patterns of prescribing.[126] Decision fatigue also contributes to

antibiotic prescribing. Physicians may see antibiotic prescriptions as

being an “easy” solution to maximize patient satisfaction; when tired,

physicians are more likely to make the easy decision. Support for

this concept comes from a study of 23 primary care practices in the

USA showing that the proportion of patients receiving an antibiotic

increased toward the end of physicians’ shifts.[127]

Consistent with this observation are the results from a large-scale

review of antibiotic prescribing in ambulatory patients with clinically

obvious respiratory infections.[103] The investigators divided motivat-

ing factors into those operating at the patient or the physician level

(Table 1). Patient factors, including specific findings related to pathol-

ogy, appear appropriate. However, physician perception of a patient’s

desire to receive antibiotics was positively associated with prescribing

in all six studies in which it was considered.[103]

The duration of symptoms influences prescription practice. Practi-

tioners who do not have a well-established relationship with a patient

fear that not prescribingwhat is expectedwill undermine patient confi-

dence in them especially if an illness lasts longer than anticipated.[128]

Nursepractitioner (NP)s andotherswithphysician-extendingpractices

are particularly vulnerable. They may suspect that patients will seek

a more qualified practitioner to get the treatment they believe they

need,[129,130] and will view the NP as not fully competent. In this sce-

nario, antibiotic-prescribing represents a demonstration of their pro-

fessional “power.”

Notably, a factor that reinforces the tendencyofGPs tomeetpatient

expectation for antibiotics is the perception that antibiotic overuse is

not a serious medical issue in their practice. An Australian study exam-

ined doctors’ perceptions of the impact of antibiotic overprescribing

for upper respiratory tract infections in a primary care practice like

their own. Most GP respondents reported that they would prescribe

antibiotics for a URI to meet patient expectations, and believed that

antibiotic prescribing inprimary carewasnot responsible for thedevel-

opment of antibiotic resistance [131]; antibiotic resistancewas believed

to be largely due to hospital prescribing, veterinary use of antibiotics,

and antibiotic use in agriculture.

Financial incentives to prescribe and dispenseantibiotics

Financial factors are major interacting drivers behind variation

in antibiotic use. Financial incentives, profiteering from insurance

schemes, and diverse forms of marketing [132] influence antibiotic pre-

scribing. Practitioners who have a financial incentive to dispensemedi-

cations prescribe more drugs. This holds true for antibiotics from Zim-

babwe and Korea to Switzerland.[133–136] Several examples illustrate

how this occurs.

In China, the financial incentives for prescribing antibiotics date

from the barefoot doctor program. Introduced in 1968, the program

is typically depicted as a strategy for good health at low cost through

provision of integrated (traditional medicine and allopathic medicine)

primary care. Less-recognized is that the program is largely respon-

sible for popularizing the liberal use of antibiotics in the countryside.

Barefoot doctors were permitted to profit from dispensing antibiotics

and this became a primary source of their income.[137] When the bare-

foot doctor program was phased out in the mid-1980s, medical prac-

titioners continued to prescribe antibiotics to obtain fees for services,

and dispensing chemists began selling antibiotics without a prescrip-

tion tomeet popular demand. A country-wide survey in China between

2007 and 2009 [138] documented substantial antibiotic overprescrib-

ing despite shifts in best practice policy advocated by the government.

TheChinesehealth sector is dominatedbyprofit-drivenhospitals oper-

ating in a “free”market in which services are largely paid out-of-pocket

bypatients.[139] Compensation for bothhospitals anddoctors is closely

tied to pharmaceutical sales (Ding et al. 2019). As such, doctors [140]

and pharmacies in China earn their livelihood frompatientswho have a

strongpreference for antibiotics and respond to this demand for antibi-

otics as means of increasing income.[141]

Although China has recently made great strides in prescription

policy, implementation lags. In a national sample, non-prescription

sales of antibiotics for pediatric diarrhea and URTIs were 48.5%

and 70.1%, respectively.[142] Moreover, because self-treatment with

antibiotics is so common,[142,143] doctors tend to prescribe more pow-

erful agents and newantibiotic combinations unknown to the public, to

differentiate their services from self-treatment. A similar phenomenon

is common in India.[144,145] Through a network of pharmaceutical

representatives (salespersons), the large pharmaceutical companies

have introduced a steady stream of new branded drugs to doctors

eager to have an edge in competitive health care markets.[146,147]

Aggressive direct-marketing and a gift culture contribute to both

over-prescription and use of proprietary drugs rather than cheaper

generics.[148,149]

Financial gain from the overuse and misuse of antibiotics is multi-

modal, and associated with both lax implementation of laws and with

outright corruption. In Europe, variation in antibiotic consumption is

correlated with measures of corruption in both the health sector, and

in society at large.[150] Uncertainty avoidance, the extent to which a

society tolerates uncertainty and ambiguity, is a major driver of antibi-

otic utilization[151] that also correlates with societal levels of corrup-

tion and bribery.

Across Europe, total antibiotic consumption has been lower in coun-

tries that restrict direct pharmaceutical marketing to physicians, and

is also lower in health systems where patients are generally required

to visit the same family practitioner.[127,128,131] Such findings suggest

that greater freedom to select a physician may exert increased pres-

sure on physicians to try to please patients in situations in which the

8 of 18 BLASER ET AL.

TABLE 1 Systematic review of studies identifying factors associated with antibiotic prescribing for respiratory tract infections (Mackey &Nayyar, 2016)

No. of studies with:

Factor

Positive

association

Negative

association

No significant

association

Total no. of

studies

Patient level

Age 6 13 19

Male sex 1 9 10

Comorbidity 2 7 9

Medical insurance type 1 7 8

Ethnicity 1 6 7

Black versus white race 1 5 6

Fever 5 1 6

Bronchitis 5 5

Purulent sputum 5 5

Respiratory findings on physical exam 5 5

Desire for antibiotics 3 1 4

Smoker 3 1 4

Cough 1 2 3

Duration of illness 1 2 3

Household income 1 2 3

Pharyngitis 3 3

Rhinorrhea 2 1 3

Sinus pain on exam 3 3

Tonsillar exudate 3 3

Tympanic membrane abnormality 3 3

Physician level

Specialty 6 2 8

Perception of desire for antibiotics 6 6

Severity of patient illness 4 4

High-volume practice 1 2 3

International medical graduate 2 1 3

Area-level

Geographic location 1 6 7

Rural versus urban 3 4 7

Year of visit 4 4

Visit location (office, emergency department, hospital clinic) 1 2 3

specific indications for treatment are not rigid, which in reality includes

most clinical scenarios. Antibiotic consumption also is greater in health

systems inwhichmore types of antibiotics are available.[152] A system-

atic review of qualitative studies assessing prescribing practice found

that the effect of pharmaceutical marketing on physicians’ decisions

was mixed. However, studies that examined financial incentives found

a positive association with prescribing.[104,153] The fact that pharma-

ceutical companies have extensive marketing practices indicates per se

that they believe that such campaigns are effective for shaping physi-

cian attitudes, and ultimately their own sales.[154]

Cultural drivers of variation

“Culture” influences local perceptions of risk and illness, health-

care seeking behavior, and trust in and expectations from healthcare

providers, including prescription practices.[155] The substantial intra-

and international differences in antibiotic prescriptions in Europe and

the United States cannot be fully explained by variation in health ser-

vice provision.[152,156–161] One productive approach to studying vari-

ation is to quantify the effect of value-oriented dimensions of cultural

differences (Table 2).[47,151,162] A few examples may be cited.

BLASER ET AL. 9 of 18

TABLE 2 Dimensions of culture used in comparative studies ofmedical practices (Hofstede, 2011)

Power distance The extent to which citizens tolerate social

inequality, and the way in which the

power differential effects doctor:patient

communication.

Uncertainty avoidance The extent to which a society tolerates or

responds to uncertainty and ambiguity;

that is, the comfort level of citizens faced

with uncertainty and the pressure for

action to gain a sense of control.

Individualism versus

collectivism

The extent to which individuality eclipses

collectivist social values.

Masculinity The extent to whichmasculine values

associated with assertiveness,

competitiveness, and stamina prevail

and arechurch attendance by socially

accepted.

Long-term versus

short-term

orientation

The extent to which pragmatic virtues

guide future-oriented behavior inclusive

of saving, persistence, and adapting to

novel circumstances.

Indulgence Extent to which a society condones and

has policies that enable gratification of

basic and natural human drives and the

pursuit of personal enjoyment.

The culture of Switzerland is strongly influenced by and reflective of

the surrounding countries of France, Italy, and Germany. Among Swiss

hospitals, those in Italian-speaking areas consume themost antibiotics,

followed by those in French-speaking and then German-speaking

areas, trends that parallel the relative usage in the three adjacent

countries.[163] Similar relationships have also been observed for

outpatient prescribing.[164] These differences within one country with

a relatively uniform medical payment and education system points

to the importance of cultural factors as determinants of antibiotic

usage.

The 2009Eurobarometer study, conducted in 27 EU countries using

cultural dimensions (Table 2), found that nearly half of the geograph-

ical variation in inappropriate antibiotic use could be explained by

two dimensions: uncertainty avoidance and masculinity.[165–167] Com-

pared with most Northern European countries, those in the Mediter-

ranean, which also have the highest per capita antibiotic use in Europe,

had far higher uncertainty avoidance scores. Increased antibiotic use

hasbeenassociatedwith intoleranceof ambiguity anduncertainty.[165]

Low uncertainty tolerancemay lead patients to respond poorly tomes-

sages that an illness (e.g., acute respiratory episode) is self-limiting,

requiring only symptomatic therapy. Doctors also are more likely to

be uncomfortable and prescribe an antibiotic when faced with symp-

tomsmost likely to due to a viral infection, but that overlap with bacte-

rial infections. High uncertainty avoidance scoresmay also help explain

intraregional differences in antibiotic use between Flemish Belgians

and adjacent Dutch residents.[165] The former has among the highest

uncertainty avoidance scores in Europe, whereas the Dutch have one

of the lowest.[168]

Countries with high masculinity scores also tend to have a strong

work ethos in which staying on the job is both respected and expected,

except for serious illness. In suchenvironments, antibioticsmaybeused

more liberally since they are seen as a means of achieving functional

health and returning to work rapidly.[165] This relationship may help

explain the high level of ambulatory antibiotic consumption in the UK

and the US, since both countries score low on uncertainty avoidance,

but high onmasculine work ethic values.

Cultural and social economic factors are closely tied to prescrip-

tion patterns at multiple levels.[155] In Germany, where antibiotic

use is much less than in France, patients are less likely to ask for

antibiotics for cough or sore throat, and physicians are more likely

to advocate waiting and ordering extra diagnostic tests.[159] Another

important reason for these differences is the price of medicines.

In France, prices of pharmaceuticals are much lower with generics

accounting for greater market share. In the past, French pharma-

cies were better compensated for dispensing more expensive drugs

that were more aggressively marketed. Similar to doctors in China,

doctors in France favored newer antibiotics such as broad-spectrum

cephalosporins, while German doctors favored more generic narrow-

spectrum antibiotics. Antibiotic consumption in Turkey has recently

increasedmarkedly, closely related to a new reimbursement policy fol-

lowing social insurance reform, a measure that facilitated antibiotic

prescription and consumption.[169]

Immigration status, not ethnicity per se, appears to contribute to

variation in pharmaceutical use. In a Dutch study, first-generation non-

Western immigrants received more antibiotics than the native Dutch

(OR 1.31, 95% CI 1.04–1.65), but this effect disappeared in the second

generation.[170] A Swedish study found that 8-month-old infants who

had both parents born outside of Sweden were more likely to receive

antibiotics (OR 1.43, 95% CI 1.24–1.65) than infants with Swedish-

born parents.[171] Although Polish, Colombian,Moroccan, andChinese

immigrants to Spain and Norway had lower antimicrobial drug pur-

chase rates than the native-born population, differences (e.g., income,

education) related to self-medication and traditional medicine use

were not studied.[147]

Regional variation in USA antibiotic use also merit considera-

tion of regional cultural differences as well as practitioner density,

demographics, and socioeconomics. Two notable USA trends include

correlation of church attendancewith both antibiotic and opioid use. A

2014 Pew poll on the religious landscape showed a pattern of church

attendance by state (Figure 2, panel C),[172] thatwas highly concordant

with antibiotic-prescribing practices (panel B). It is improbable that

receiving antibiotics makes individuals more likely to go to church, or

that people who regularly attend church have more infections that

require antibiotics. More likely, factors that predispose to church

attendance may affect likelihood of taking antibiotics; these need not

be exclusive. One such factor may be uncertainty avoidance; church

attendance provides a means of coping with uncertainty, since figures

of higher authority (be it God, preachers, or doctors) offer solace and

reassurance. Another factor might include regional differences in

approaches to problem-solving. Regions with high attendance/usage

patterns might rely more extensively on externalities -religious belief

10 of 18 BLASER ET AL.

as an approach for societal and spiritual problems, and medical belief

in antibiotics as an approach to bodily problems.

Notably, in the USA, states with the highest antibiotic rates are

predominantly Protestant. This is apparently at odds with the hierar-

chical values hypothesis noted above. Catholicism is more hierarchical

than Protestantism and in Europe is associated with higher antibiotic

rates.[173,174] However, fundamentalist churches in the Southern

and Central US are often led by charismatic preachers who promote

authoritarianism.[175] The ethos of these regions has been associ-

ated with a high need for security, adversity to uncertainty, fear of

contagion, and inclination to support those who provide order and a

sense of control,[176,177] characteristics consistent with relatively high

antibiotic prescribing.

In the USA, there also is a strong correlation between higher pre-

scription rates for antibiotics and opioid pain relievers in the individual

states[178] [Figure 2, panel A]. One possibility is that practitioners who

over-prescribe antibiotics provide more prescriptions in general. Since

the medications treat entirely different types of problems, this corre-

lation might reflect distribution and type of prescribers providing ser-

vices, and/or the culture of prescribing, which might be influenced by

levels of socioeconomic insecurity and of patient education.[19] Prac-

titioners serving impoverished patients may consider the life circum-

stances of patients beyond their present illness; antibiotics and pain

killers may be prescribed as stop-gap measures for their chronic ill

health trajectories. The economics of medical practice also may be rel-

evant, since in many states, a small number of prescribers account for

disproportionate opioid prescriptions. The economic considerations

may parallel antibiotic-prescribing to avoid losing customers.

Other differences and observations requiring furtherinvestigation

A patient’s sex is an important variable related to antibiotic overuse.

In the USA in 2011, prescription rates for females were almost double

those for males.[19] The highest rates were in census tracts with the

fewest college graduates, and those with the lowest median income.

These data suggest that poorer, less-educatedwomen receive farmore

antibiotics than do their more-affluent better-educated peers. Does

this merely reflect differences in general health, or do other social and

cultural factors affect prescribing?

Globally, increases in both Gross Domestic Product (GDP) and

physician density have been associated with increased antibiotic con-

sumption in LMICs, but not in HICs, for reasons that are not clear.[2]

Another relevant health service consideration is the autonomy of

physicians indecision-makingor consultingwithpeers andotherhealth

professionals. For example, Belgium, among the European countries

with high antibiotic prescribing rates, shares cultural similarities to the

neighboring Netherlands where antibiotic use is low,[157] but struc-

tural differences in health care system organization may be relevant.

TheNetherlands, unlikeBelgium, has a systemof family physician peer-

review groups that encourages collaboration and auditing with phar-

macists. However, consultations about respiratory tract infections are

higher in Belgium than the Netherlands, and differences in prescribing

quality are notable.[179]

In several European countries, religious affiliation and church atten-

dancehasbeendeclining.[180] Might this reflect onantibiotic usage?An

analysis of European countries showed that atheists consumed fewer

antibiotics per capita than those in the same country with a religious

affiliation. However, atheists harboring more distrustful attitudes had

higher rates of antibiotic consumption.[152] A related issue to consider

is the impactof vaccination coverageonantibiotic use.Vaccination cov-

erage rates correlatewith antibiotic useglobally; theproportionof chil-

dren being vaccinated for measles has been inversely associated with

antibiotic consumption.[2] This could reflect direct and indirect vac-

cine impact on children’s health,[181,182] ormaymirror broadermedical

practices. Although these are correlations, they generate hypotheses

about the impact of ideology, trust, and authority on behavior related

tomedicines at individual and population levels. [183,184]

Finally, the global pandemic of COVID-19 has affected antibiotic

usage as it has so many other aspects of healthcare. Early in the out-

break, when physicians were faced with severely ill patients with high

fevers, even though they knew that the ultimate cause was a virus

(SARS-CoV-2), they began empiric antibiotic treatment for suspected

bacterial superinfection out of proportion to the real indications.[185]

In themoment of crisis, antibiotic use for suspectedbacterial infections

was the default approach, regardless of indication. Physicians cared

deeply for their critically ill patients, and with a dearth of evidence,

responded with the now time-honored approach, empiric antibiotics;

whether these improved or worsened outcomes was not determined.

In some other critically patients, there has been fear of antibiotic toxic-

ity that may be disproportionate to their benefit.[186] Thus, the appro-

priate use of antibiotics in critically ill patients is complex; fortunately,

such patients represent a very small proportion of all of the people

receiving antibiotics.

SYNTHESIS AND PROSPECTS

Antibiotics began to bewidely deployed in the 1940s, following univer-

sal acknowledgment of their salutary properties. Consequently, now

>75 years after their introduction, antibiotic use has grown enor-

mously around the world. Antibiotics have become a pillar of contem-

porarymedicine affecting essentially all areas of practice. In this article,

we consider six general observations relating to their overuse.

Concepts underlying use variation and overuse

First, the dictum “Primum non nocere” (first do no harm), a basic tenet

of medicine, demands that potential benefits and risks of any practice

must be weighed. Practitioners must use agents when net benefit

exceeds net risk. Until recently, antibiotics have generally been per-

ceived to incur minimal risk to their recipients beyond short-term side

effects, and medical conditions in which benefits exceed apparent risk

have been numerous. In consequence, high proportions of patients are

BLASER ET AL. 11 of 18

prescribed antibiotics for primary conditions or for prophylaxis. Given

current knowledge about antibiotic resistance[2] and antibiotic impact

on the microbiome,[14] such practices are now being challenged. The

true benefit/risk ratio of antibiotic use for specific medical conditions

is being re-examined, and best practice guidelines revised in the

face of emerging evidence that remains largely unknown to general

practitioners and the public. General patterns of practice substantially

lag behind advances in any field.

A growing body of studies now point to substantial previously

unrecognized risks associated with antibiotic use. Over the past 15

years, it has become clear that the humanmicrobiome is a central actor

in human physiology,[187,188] with many functions deeply integrated

into human biology. It has also become clear that the microbiome

of people in industrialized countries differs markedly from that of

peoples in more traditional societies all over the world, regardless of

their location, ethnicity or diet.[189] As cited earlier,[13–16] there now

is a wide body of evidence that exposure to antibiotics over these past

75 years is a major factor in these changes. The greatest emphasis has

been on antibiotic usage in young children, with respect to altering the

microbiome at the very time that host immunological, metabolic, and

neural systems are developing [190–195]; and epidemiological studies

associate antibiotic exposure with an increased risk of disease of aller-

gic, metabolic, and cognitive disorders that have grown more common

in children during the antibiotic era.[196] However, there is increasing

evidence in adults that antibiotics also may enhance risk for metabolic

and neoplastic diseases, including diabetes, kidney stones,[197] and col-

orectal adenomas.[198–200] As evidence accumulates about the biologi-

cal costs of antibiotic use, using knowledge gained from environmental

approaches,[201] there is greater need for more rational antibiotic

usage. Practitioners have an incomplete understanding about these

concepts.Messages about the harmof taking antibiotics typically focus

on side effects and drug resistance, but the emerging knowledge of

long-term effects on the microbiome has not substantially penetrated

the clinical realm. Finally, the concepts that practitioners learned about

broad-spectrum and narrow-spectrum antibiotics needs to be brought

up to date. These concepts are tied to an antibiotic’s ability to suppress

common pathogens, but there was no consideration of their effects on

the microbiome, which largely is composed of anaerobic bacteria; as

such, a “narrow” spectrum agent like penicillin hasmuch deeper effects

than a “broad” spectrum agent like ciprofloxacin.[202]

Second, driving overuse is the widespread belief among the general

public that antibiotics are beneficial for a broad array of conditions.

These extend beyond the treatment of specific illness to disease pre-

vention and even pain management. Perceptions of quality of care by

the public often include liberal antibiotic prescribing. The public infat-

uationwith antibiotics both fuels self-use andmakes it harder for prac-

titioners to resist the demand to prescribe them.

Third, a general featureof health transitionhasbeena falling thresh-

old of tolerance of illness. People have become less willing to wait and

let an illness run its course. The perception that there is a pill for ills

of all kinds leads the public to demand immediate relief for symptoms

from practitioners and to self-medicate. Antibiotics are widely seen as

insuring that an illness will not becomeworse and be resolved quickly.

Fourth, antibiotic use has become a crutch by those who cannot

afford to miss work due to work policies that do not provide paid sick

leave. Whether for themselves or for their children in day care, antibi-

otic use has been used as a quick fix for families that are struggling,

when the underlying problems often are related to social inequities.

Compounding the problem is that some day care centers exclude sick

children for fear of spreading of infection, and demand that they be

receiving antibiotics before being readmitted.[203,204]

Fifth, economics matter. The business practices in the competitive

health care marketplace operate to generate income. In countries in

which antibiotics can only be dispensed by prescription, their avail-

ability through the health practitioner brings many potential patients

their way, but it carries risk for the practitioner. When patients inap-

propriately demandantibiotics, practitionersdiffer in their ability, time,

anddesire todissuadepatients fromunnecessary usage. In competitive

medicalmarket places, practitioners are concerned about doctor shop-

ping and the reputational consequences of withholding antibiotics as

a means of enacting antimicrobial stewardship,[205] and in countries

where antibiotics are commonly purchased over the counter, practi-

tioners are motivated to prescribe “stronger” antibiotics to differenti-

ate from the dispensaries of untrained practitioners and pharmacists.

In LMIC where antibiotics are available without prescription, they

often are purchased over the counter, and this wide availability affects

prescribing at multiple levels. Pharmacy attendants who directly dis-

pense medicine are privy to the steady stream of prescriptions they

see daily, often mimicking the agents used. Pharmaceutical represen-

tatives frequently visit doctor’s offices and chemist shops, monitor

sales, and offer economic incentives for prescribing their products,

especially the more expensive agents. An intrinsic conflict of interest

exists between optimal care for patient and the financial well-being

of the provider. Such issues cannot be fully addressed by regulation,

and require greater oversight, professional responsibility, accountabil-

ity and systems of payment that emphasize keeping people healthy

rather than treating disease episodes.

Sixth, lack of continuity of care and time for effective communica-

tion lower the trust necessary to convince patients that they do not

require antibiotics (or other medications) to recover from illness. With

the episodic care that exists on the openmarket in most locales, incen-

tives are aligned that lead to over-prescribing.

Approaches to solving the problem

It is beyond the scopeof this paper to critically reviewdataon theeffec-

tiveness of interventions aimed at antibiotic stewardship. Education

of both practitioners and the public is necessary, but not sufficient, to

deal with the global antibiotic overuse criseswe are facing.[206] In clos-

ing, we offer several recommendations for those seeking to raise con-

sciousness about the harms of antibiotic overuse and the urgent need

to change current practices.

1. Primary care providers need to be convinced that their outpatient

practices are in fact contributing to the antibiotic resistance

12 of 18 BLASER ET AL.

problem in a substantial way. Antibiotic overuse education also

needs to reflect concerns about the microbiome (and related

cultural concepts focusing on human ecology) and long-term

health promotion and not exclusively on antibiotic resistance.

Such messaging needs to be balanced with acknowledging the

clear-cut beneficial uses of antibiotics. One solution is to use “social

norms” (“how others consider my behavior”) as an approach, since

such initiatives have reduced smoking behaviors, for example.[207]

Employing norms has been used to affect physician behavior,[208]

but the results with relation to antibiotic use have been

mixed.[209–211]

2. Practitioners must learn about better ways to communicate about

antibiotic risks and benefits at levels appropriate to all patients, and

to have tools that provide for greater flexibility of prescribing. Pro-

viding the necessary information for them will require culturally

sensitive translational research that addresses popular misconcep-

tions. The role of the health practitioner as onewho carefully evalu-

ates a patient’s health status, provides a correct diagnosis, and pre-

scribes medication as needed, should supplant the current domi-

nant role of practitioner as medication dispenser.

3. Communication related to antibiotic overuse must be illness-

specific and not just general, consistent with what we have learned

in the past about health communication, for both clinicians and

patients.

4. Alternatives to antibiotics need to be identified for populations that

are highly medicalized and pharmaceuticalized[212,213] and who

demand a medication to replace antibiotics, providing the patient

with a sense of agency and control. More research is needed about

the potential roles or not of probiotics in place of antibiotics.[214]

5. Antibiotics are a commongood. Their use is too important to be cor-

rupted by financial incentives. Steps must be taken to eliminate as

far as possible, systemic economic factors driving antibiotic overuse

at all levels.

6. To address antibiotic overuse, globally as well as locally, it will be

necessary to examine social, structural, and commercial determi-

nants of prescription practices, over the counter sales, and self

medication.

CONCLUSIONS AND OUTLOOK

The prescribing and use of antibiotics are at the intersection of

medicine, economics, and belief systems. Widely considered as “mira-

cle drugs,” antibiotics have been overused across the globe, but at dif-

fering levels reflecting the confluence of local factors. The increasing

knowledge of how antibiotics are affecting the humanmicrobiomewill

lead tomore restraint in their acceptanceand in their use. Suchchanges

will not come too soon, because we already are observing extinctions

of ancestral taxa that have been linked to the increasing burden of non-

communicable diseases happening everywhere. This phenomenon, due

to the unintended consequences of human progress, resembles the

macro-ecologic process of climate change, but at the micro-ecological

level. It is probably occurring at a faster rate than climate change,which

is why we must ameliorate antibiotic overuse as soon as possible. We

must consider this to be another part of restoring our planetary health;

learning from the fight against climate change may provide tools and

approaches to gain control. Global variation in human antibiotic pre-

scription and overall utilization a priori indicates that use has not been

optimized for patient care and societal benefit. It took75years to reach

the present point of crisis. We are currently at a tipping point; the

health and well-being of future generations requires that we reverse

current trends of antibiotic misuse. Such action requires recognizing

the many drivers of this complex phenomenon and concerted efforts

to deal with each in their proper context.

ACKNOWLEDGMENTS

Supported in part by CIFAR (Humans and Microbiome Program), U01

AI22285 from theNational Institutes of Health, Transatlantic Program

of Fondation Leducq, and the Zlinkoff and C & D funds. The authors

thankKrystCedeno for her editorial assistance andNafadeVaidehe for

her initial contributions to the research.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ORCID

Martin J. Blaser https://orcid.org/0000-0003-2447-2443

MelissaK.Melby https://orcid.org/0000-0003-1766-5466

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How to cite this article: Blaser, M. J., Melby, M. K., Lock, M.,

Nichter, M. (2021). Accounting for variation in and overuse of

antibiotics among humans. BioEssays, e2000163.

https://doi.org/10.1002/bies.202000163